Functional relevance of tetraspanin CD9 in vascular smooth muscle cell injury phenotypes: A novel target for the prevention of neointimal hyperplasia
Functional relevance of tetraspanin CD9 in vascular smooth muscle cell injury phenotypes: A novel target for the prevention of neointimal hyperplasia
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DOI：
10.1016/j.atherosclerosis.2008.07.036
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发表时间：
2009-04-01
期刊：
影响因子：
5.3
通讯作者：
Jennings, Lisa K.
中科院分区：
文献类型：
--
作者：
Kotha, Jayaprakash;Zhang, Chunxiang;Jennings, Lisa K.
血管平滑肌细胞（VSMC）的迁移和增殖是血管损伤后新生内膜形成的关键因素。在这项研究中，我们发现，CD 9是组成性表达的血管平滑肌细胞的新生内膜损伤的颈动脉。与对照抗体处理相比，通过用CD 9特异性单克隆抗体mAb 7处理，人冠状动脉平滑肌（hCASM）细胞的体外迁移和增殖分别降低40%和63%。在小鼠颈动脉结扎损伤模型中，单次应用中和抗小鼠CD 9抗体导致新生内膜形成减少31%（第14天，n = 8，p < 0.05）和32%（第28天，n = 5，p < 0.01）。为了支持这些发现，通过CD 9-腺病毒转导外源性表达人CD 9导致新生内膜增加43%（p < 0.05，n = 6）。在研究CD 9介导的VSMC表型事件的潜在机制后，我们发现整合素α 5 β 1是CD 9的组成性伴侣，并且CD 9显著增强PI-3激酶依赖性Akt磷酸化。此外，增强的Akt磷酸化被mAb 7结合减弱。累积起来，已经证明了CD 9、α 5 β 1、PI 3-K/Akt活性与增强的VSMC迁移和增殖表型之间的功能联系。这些研究表明，调节CD 9介导的VSMC表型的药物可能成为治疗异常血管损伤反应的新策略。出版社：Elsevier爱尔兰Ltd.
Vascular smooth muscle cell (VSMC) migration and proliferation are critical events in the development of neointima following vascular injury. In this study, we found that CD9 is constitutively expressed in the VSMC of the neointima of injured carotid arteries. The in vitro migration and proliferation of human coronary artery smooth muscle (hCASM) cells were reduced by 40% and 63%, respectively, by treatment with a CD9 specific monoclonal antibody mAb7 when compared to control antibody treatment. In a mouse carotid ligation injury model, a single application of a neutralizing anti-mouse CD9 antibody resulted in a 31% (day 14, n = 8, p < 0.05), and 32% (day 28, n = 5, p < 0.01) reduction in neointima formation. In support of these findings, exogenous expression of human CD9 by CD9-adenoviral transduction led to 43% increases in neointima (p < 0.05, n = 6). Upon investigation of the mechanisms underlying CD9 mediated VSMC phenotypic events we found that integrin alpha 5 beta 1 was a constitutive partner of CD9 and that CD9 significantly augmented PI-3 kinase dependent Akt phosphorylation. Furthermore, enhanced Akt phosphorylation was attenuated by mAb7 binding. Cumulatively, a functional link between CD9, alpha 5 beta 1, PI3-K/Akt activity and enhanced VSMC migratory and proliferative phenotypes has been demonstrated. These studies suggest that agents that modulate CD9 mediated VSMC phenotypes may emerge as novel strategies for the treatment of abnormal vascular injury response. Published by Elsevier Ireland Ltd.